1. Field of the Invention
This invention relates to chemical compounds in medicine, and more specifically to fluoro-containing derivatives of hydrogenated pyrido[4,3-b]indoles with neuroprotective and cognition enhancing properties, process for preparing and use.
2. Description of Related Art
Under normal physiological conditions, excitatory amino acids (“EEAs”) are involved in the neural pathways associated with learning and memory [Wang H., Hu Y., Tsein J. Z. Molecular and systems mechanisms of memory consolidation and storage. Prog. Neurobiol. 2006; 79(3):123-35]. A variety of neurological disorders and neurodegenerative diseases, such as Alzheimer's disease (“AD”), Huntington's disease (“HD”), amyotrophic lateral sclerosis (“ALS”) and brain ischemia are associated with an excitotoxic effect of endogenous neuromediatory excitatory amino acids, such as glutamic and aspartic acids [a) Stemmer J. E., De Zeeuw C. I., Weber J. T. Don't get too excited: mechanisms of glutamate-mediated Purkinje cell death. Prog. Brain Res. 2005; 148:367-90; b) Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. 1999; 81(3):163-221]. In accordance with this mechanism, hyperexcitation of neurons (i.e. prolonged activation of their NMDA, AMPA/kainate receptors with EAA) results in excessive entry of calcium ions into the neuronal cells [Kwak S., Weiss J. H. Calcium-permeable AMPA channels in neurodegenerative disease and ischemia. Curr. Opin. Neurobiol. 2006; 16(3):281-7]. Calcium influx into an NMDA channel takes place following an action potential when a glutamatergic presynaptic neuron releases glutamate molecules into a synapse. The released glutamate interacts with the catalytic site of the NMDA receptor on the post-synaptic neuron and, once the channel is freed of magnesium that occupies it under rest conditions, allows calcium influx from the extracellular medium into the intracellular medium. If the NMDA channel remains open to the calcium influx for more than a few milliseconds (pathological conditions), a cascade of intracellular reactions is initiated, leading to neuronal death (apoptosis).
Accordingly, the NMDA receptor is an attractive and validated target for the treatment of AD [Samanta M. K., Wilson B., Santhi K., Suresh B. Alzheimer disease and its management: a review. Am. J. Ther. 2006 November-December; 13(6):516-26]. Therapeutic intervention may take place either by blocking the influx of calcium ions (“corking-up” the channel) [Albensi B. C., Ilkanich E. Open-channel blockers of the NMDA receptor complex. Drug News Perspect. 2004; 17(9):557-62] or by interaction with the NMDA receptor binding site. Research indicates that NMDA receptor antagonists have the potential to prevent injury and death of neurons related to a variety of conditions [Gerber A. M., Vaallano M. L. Structural properties of the NMDA receptor and the design of neuroprotective therapies. Mini Rev. Med. Chem. 2006; 6(7):805-15], including ischaemic cerebral pathologies, neuropathic pain, ALS, AD [Wenk G. L. Neuropathologic changes in Alzheimer's disease: potential targets for treatment. J. Clin. Psychiatry 2006; 67 Suppl. 3:3-7; quiz 23], HD, and AIDS-related dementia.